HRP920514A2 - Process for preparing ligands nitrogenous cycle - Google Patents

Abstract

Ligands and complexes of the title and the applications of these complexes in magnetic resonance imaging, in X-ray radiology and as in-vivo chemical shift agents.

Description

The technical field to which the invention belongs

The invention is from the field of synthetic chemistry and refers to the creation of new metal complexes with cyclic organic ligands.

Technical problem

The technical problem solved by the present invention is a process for obtaining new metal complexes with chilic organic ligands.

The invention ensures obtaining complexes that are formed from ligands of the general formula:

[image]

where:

R1 represents the radical of the formula:

[image]

R6 is selected from the group consisting of C1-C4 alkyl, C1-C14 hydroxyalkyl, C1-C4 polyhydroxyalkyl and a group of the formula:

[image]

R11 is selected from groups A and groups of the formula

[image]

A is selected from the group consisting of C1-C8 alkylene, C1-C8 hydroxyalkylene and C1-C8 polyhydroxyalkylene,

[image] R7 is selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group,

m = 0 or 1,

R2, R3, R4 are identical or different and represent the radical formula:

[image]

R1 and R1 are identical or different and are selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group,

p = 1 or 2

n = 0, 1, 2 and

R5 is selected from the group consisting of a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group and

Z is selected from a hydrogen atom, an oxygen atom and a group of the formula:

[image]

R10 is selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group, a group of the formula

[image]

where R5 has the previously given meaning, and a group of the formula:

[image]

R 12 is selected from the group consisting of C1-C8 alkylene groups, C1-C8 hydroxyalkylene groups and C1-C8 polyhydroxyalkylene groups, and with metal ions selected from lanthanide ions with atomic numbers 57 to 71, with transition metal ions with atomic numbers 21 to 29 and with metal ions having atomic numbers 55, 56, 82 and 83, as well as for obtaining salts of these complexes with mineral bases or with organic pharmaceutical acceptable bases or with basic amino acids.

State of the art

Metal complexes formed with cyclic nitrogen ligands of the above-defined general formula (I) have not been described in the literature so far, and therefore there are no literature data for their preparation.

Description of the solution to the technical problem with implementation examples

The procedure is implemented in the following way. First, ligands of the above formula (I) are made by reacting the compound of the formula:

[image]

in which R5 has the meaning given above and X represents one labile group such as a chlorine, bromine or iodine atom or a tosyloxy or mesyloxy group, with a cyclic amine of the formula

[image]

wherein R 2 , R 3 , R 4 and n have the meanings given above,

R'1 represents the radical of the formula

[image]

R'6 is selected from a C1-14 alkyl group, a C1-4 hydroxyalkyl group, a C1-4 polyhydroxyalkyl group and a group of the formula

[image]

where R 2 , R 3 , R 4 , R 7 R 11 , m, n have the meanings given above and Z' is selected from an oxygen atom and a group of the formula

[image]

R'10 is selected from a hydrogen atom, a C1-14 alkyl group, a C1-4 hydroxyalkyl group, a C1-4 polyhydroxyalkyl group and a group of the formula

[image]

where R 1 , R 2 , R 3 , R 4 , R 12 and n have the meanings given above.

Ligands of the formula I can also be obtained by the Strecker reaction, namely by the reaction of the cyclic amine of the formula III with the aldehyde of the formula:

R5-CHO

in which R5 has the meaning given above, in the presence of hydrocyanic acid or cyano ions in general (KCN, NaCN)

A compound of formula III wherein Z' is a group

[image]

can be obtained

a) by the polyamine reaction of the formula

[image]

in which n, R'1 and R4 have the meaning given above and R' represents a tosyl, mesyl or benzenesulfonyl group, with a compound of the formula

[image]

in which R2, R3 and R' have the meanings given above and X represents a labile group such as tosyloxy, mesyloxy or a chlorine, bromine or iodine atom, or

b) by the reaction of the amine of the formula

[image]

wherein R'1 and R' have the meaning given above, with the compound of the formula

[image]

This cyclization reaction is conveniently carried out in the presence of a phase transfer catalyst.

Polyamines of formula IV can be obtained starting from dihydroxylamine according to the following scheme:

[image]

In one variant, the phthalimide of the compound of formula VII can be reacted with the compound of formula IX.

The compounds of formula II contain two nitrogen atoms in the ring and can be obtained according to the procedure defined earlier.

This can be by reacting polyamines of the formula

[image]

in which A and R' have the meanings given together with a compound of formula XI to obtain a compound of formula III in which R 11 is group A.

The polyamine of formula XII can be obtained starting from the tetrahalogen derivative by nucleophilic substitution in the presence of sodium azide and then reduction in the presence of hydrogen and palladium on carbon.

In a variant, the compound of formula I having two nitrogen atoms in the ring and where R 11 is a group can be obtained by condensation of the compound of formula

[image]

with a polyamine of the formula,

[image]

Which is further followed by reduction to diborane, according to the procedure given by Tabushi et al. (Tetra Letters 12, 1049, 1977).

Compounds of formula I containing two ring nitrogen atoms are then prepared starting from compounds of formula III in two steps as previously described.

In a variant, compounds of formula I containing two nitrogen atoms in the ring can be obtained by condensation of compounds of formula I in which R1 is a radical of the formula

[image]

where R 1 is a hydroxyalkyl group, with a compound of bifunctional activity of the formula

X1 - A - X1

where X1 is a COOH, COCl or acid anhydride group.

Compounds of the formula I in which two nitrogen atoms are present in the ring can also be obtained by condensation of the compounds of the formula.

[image]

in which R''1 is a radical of the formula

[image]

where m and R7 have the meanings given above and R''6 is selected from a C1-4 alkyl group, a C1-4 hydroxyalkyl group and a C1-4 polyhydroxyalkyl group,

with the compound formula

X - R'12 - X

where X has the meaning given above and R'12 represents the group R12 protected.

Therefore, compounds of the formula are obtained:

[image]

This invention, in another aspect, is a process for building complexes formed by ligands of the formula I with metal ions selected from lanthanide ions (serial number 57-71), transition metal ions (serial number 21-29), Mn2+, Fe3+ and Cr3+ ions, metal ions of numbers 55, 56, 82 and 83, further salts of complexes with mineral or organic pharmaceutically acceptable bases or basic amino acids.

Gadolinium, europium, dysprosium, iron (Fe3+) and manganese (Mn2+) ions are preferred in these complexes.

Examples of salts include those enriched with sodium hydroxide, N-meylglucamine, diethylamine, lysine and arginine.

Complexes can be obtained by reaction of ligands with salts or oxidations of metals in aqueous solution and possibly by neutralization to form salts.

It can be said that this invention covers not only the ligands of formula I and the complexes previously defined in the form of a racemic mixture, but equally the stereoisomers of these ligands and complexes.

The complexes according to the invention can be attached to another macromolecule that is capable of fixing preferably to an organ. That is, the complexes according to the invention can be bound to proteins and especially antibodies.

They can also be encapsulated, especially in liposomes.

The complexes according to the invention endowed with paramagnetic ions and their salts with pharmaceutically acceptable bases can be used as contrast agents for magnetic resonance imaging and as agents for chemical changes in vivo.

The complexes according to the invention are endowed with lanthanide ions (serial numbers 57-71) or metal ions of serial numbers 55, 56, 82 and 83 and their salts with pharmaceutically acceptable bases can be used as contrast agents in X-ray radiography. For this effect, complexes enriched with ions of the following metals are particularly desirable: Gd, Er, Dy, Tb, Ce, La, Ba and Cs.

The subject of this invention is therefore a procedure for obtaining a preparation for diagnosis that is introduced into the human body, characterized by the fact that this agent is a complex endowed with a ligand of the formula I with metal ions selected from lanthanide ions, transition metal ions and metal ions of serial numbers 55, 56, 82 and 83, as well as salts of these complexes with mineral or organic bases, pharmaceutically acceptable or basic acids in a pharmaceutically acceptable form.

These preparations can be prepared mainly as solutions in water as a solvent of the physiologically acceptable complex according to the invention.

The diagnostic preparations obtained according to the invention can be administered in the following ways:

- parenterally, i.e. intravenously, intraarterially, intralymphatic and subcutaneously

- orally

- under the arachnoid meninges

- intrabronchially in the form of an aerosol

- inter-articular

- local for visual observation of cavities (for example the uterus)

In magnetic resonance imaging, doses are highly variable depending on the route of administration.

For intravenous or intra-arterial administration, the dose is about 0.01 to 2 mM/kg.

For oral administration, this dose can go up to 10 mM/kg.

For other forms of introduction, the doses used are generally below 1 mM/kg and the same for subarachoid brain membrane below 0.05 mM/kg

When used as an agent for chemical changes in vivo and as a contrast agent in X-ray radiology, the doses are the same, while for intravenous and intra-arterial administration, the doses are below or equal to 5 mM/kg.

In addition, the complexes according to the invention are endowed with ligands of formula I with radioactive ions whose salts with bases are pharmaceutically acceptable and can be used as diagnostic agents or in nuclear medicine therapy. Examples of radioactive ions are radioisotopes of elements such as copper, cobalt, gallium, germanium, indium and especially technium (Tc 99m).

The following examples illustrate the preparation of the compound according to the invention.

In these examples:

NMR spectra were recorded on a Varian EM 360 at 60 MHz with TMs as an internal reference. The solvent is CDCl3, except when there are contraindications.

IR spectra were recorded on a Perkin-Elmer 1320 apparatus. Spectra of solid substances were recorded in the form of KBr lozenges. In the case of liquids (oils), the spectra are recorded without solvent.

The term "buffer" used herein in thin layer chromatography refers to a mixture of 1.5M NH4OH and 1.5M (NH4)2CO3.

Solubility points were determined on a Kofler apparatus.

The terms used here for doses during complexation "absence of free Gd3+ and free ligand" indicate the limits of detection of the methods used, ie between 4 and 5 ppm for Gd3+ and ligand.

Example 1

Preparation of 2,6-dimethyl-1,4-7,10-tetra-azacyclododecane-N,N',N'',N'''tetraacetate acid

a) Preparation of N-tosyl-bis (2-tosyloxypropyl) amine

To a solution of 248 g (1.3 moles) of tosyl chloride in 200 cm3 of pyridine at 0ºC, a solution of 53.2 g (0.4 moles) of diiso-propanolamine in 50 cm3 is added dropwise into a container that is kept at a temperature between 0 and 5ºC by cooling. . The mixture is left at this temperature for 72 hours. The mixture is then poured into two liters of a mixture of water and ice containing 250 cm3 of concentrated hydrochloric acid.

The tosyl derivative is extracted with 2 liters (l) of methylene chloride. The organic phase is poured onto sodium sulfate, filtered and decolorized on black 3 SA and refiltered on a layer of silica. After evaporation of the solvent, 193.8 g of yellow oil remains (yield 81%; Rf = 0.7 silica/CH2Cl2/acetone/98/2), which is used further for reactions without purification.

1H NMR spectrum: 6H CH3 (doublet 1.2 and 1.3 ppm); 9H CH3 tosyl (singlet 2.5 ppm); 4H CH2 (multiplet center at 3.3 ppn); 2H CH (quadruplet between 4.7 and 5.1 ppm); 12H aromatics (multiplet 7.2 and 8 ppm).

b) Preparation of N-tosyl-bis (2-azidopropyl) amine

65.1 g of sodium azide (1 mol) was added to 193.8 g (0.32 mol) of the compound obtained in A) and 1.2 l of acetonitrile and 300 cm 3 of water. The mixture was stirred and heated at 75ºC for 48 hours. After cooling, the acetonitrile was evaporated under vacuum.

The residue was taken with 1 l of methylene chloride. The organic phase was washed with water, dried and filtered on a layer of silica (200 g). After evaporation, 82 g of light yellow oil remains (yield 75%; Rf = 85 images CH2Cl2/acetone/92/2) pure enough for further direct use.

The spectrum of IC N3 = 2100 cm-1 is intense.

c) Preparation of N-tosyl-bis (2-aminopropyl amine)

82.2 g (0.244 mol) of the compound obtained in b) is poured into 500 cm3 of ethanol containing 8 carbons per palladium and that is 5% at a humidity of 50%.

The mixture is stirred vigorously while hydrogen is slowly introduced (evacuation of the released nitrogen). After 8 hours at room temperature, CCM shows the absence of azide function. The mixture is then filtered and evaporated. 68.4 g of light yellow oil is obtained (yield 98.5%, Rf = 0.6 silica/MeOH/NH4OH 95/5) which is used without further purification.

NMR spectrum: 6H CH3 (doublet 0.9 and 1ppm); 3H CH3 tosyl (singlet at 2.4 ppm); 6HCH2 and CH (a massive complex between 2.7 and 3.2 ppm); 4H aromatics (multiplet between 7.1 and 7.7 ppm).

d) Preparation of N-tosyl-bis/2 (tosylamino) propyl/amine

To 68.4 g (0.24 mol) of the main obtained in c) in 500 cm3 of methylene chloride and 700 cm3 (0.5 mol) of triethylamine at 0ºC was added 93 g (0.5 mol) of tosyl chloride in portions. After the addition was complete, the mixture was left for 6 hours at room temperature with stirring. The reaction mixture is washed with 600 cm3 of water, the organic phase is dried, evaporated to dryness and the residue is chromatographed on a silica column with methylene chloride and then with a methylene chloride/methanol/98/2 mixture. The fractions of interest were evaporated, the solid residue was recrystallized in ethanol. After filtering and drying, a mass of 99.1 g is obtained (yield 79%)

NMR spectrum: 6H CH3 (doublet 0.0 lppm); 9H CH3 tosyl (singlet 2.4 ppm); 4H CH2 (triplet center at 2.9 ppm); 2H CH (doublet 3.3 and 3.5 ppm); 12H aromatic (multiplet centered at 7.4 ppm).

e) Preparation of N-tosyl-bis (2-tosyloxy ethyl) amine

To a solution of 185 g (0.97 mol) of tosyl chloride in 220 cm3 of pyridine at 0ºC is added a solution of 32.5 g (0.31 mol) of diethanolamine in 60 cm3 of pyridine so slowly that the temperature does not exceed 5ºC. After the addition, the mixture is maintained for 1 hour at this temperature and then poured into 220 cm3 of ice water with good stirring. After filtering, washing and drying, 148.4 g of precipitate is obtained. (yield 85%; Rf = 0.6 silica/CH2Cl2/acetone/98/ 2).

NMR spectrum: 9H CH3CO tosyl (singlet 2.4 ppm); 4H CH2N (triplet at 3.4 ppm); 4H CH2O (triplet at 4.1 ppm); 12H aromatics (multiplet between 7.1 and 7.7 ppm).

f) Obtaining N, N', N'', N''' tetratosyl-2-6-dimethyl-1,4,7,10-tetraazacyclododecane

65 g (0.11 mol) of the compound obtained in D) cast into 500 cm3 of dry DMF is added dropwise to a vessel containing 8.8 g (0.22 mol) of 60% NaH in oil in 50 cm3 of DMF. The addition is done at room temperature and so that the release of hydrogen is regulated. at the end of the addition, the mixture is heated to 100ºC, a solution of 68.1 g (0.12 mol) of the compound obtained in e) above in 500 cm3 of dry DMF is added dropwise to the container. The reaction mixture is maintained for 24 hours at this temperature with good stirring.

The solvent is then evaporated under vacuum and the residue is reintroduced into the CH2Cl2/H2O mixture. The organic phase is washed with water, dried and evaporated to dryness. The residue (100 g) is recrystallized in isopropanol, then in propanol to obtain, after filtration, washing with isopropyl ether and drying, 36 g of a white solid (yield 40%; Rf = 0.5-0.6 silica (CH2Cl2/acetone/ 98/2).

NMR spectrum: 6H CH3 (doublet at 1 and 1.2 ppm); 12H CH3 tosyl (singlet 2.4 ppm); 14H CH2 and CH (massive between 3 and 4.5 ppm); 16 H aromatics (multiplet between 7.1 and 7.7 ppm).

g) Preparation of N, N', N'', and N''-tetratosyl-2-6-dimethyl-1,4,7,10-tetraazacyclododecane (variant)

A solution of freshly prepared sodium ethylate (60 mmol) in 200 cm3 of dry DMF was quickly added to the suspension of 17 g (28.7 mmol) of the compound obtained in d) in 100 cm3 of ethanol at reflux. The resulting mixture is not clear and is left to reflux for half an hour. The solvents are then evaporated to dryness, the residue is taken with 200 cm3 of DMF and heated to 100ºC. A solution of 17 g (30 mmol) of the compound obtained in e) in 100 cm3 of DMF is added to this solution over half an hour. The reaction mixture was kept at 100ºC overnight. The DMF is immediately evaporated and the residue is taken up with a mixture of H2O/CH2Cl2. The resulting organic phase product was chromatographed on a silica column with a CH2Cl2/ethyl acetate/98/2 mixture as eluent. The product was recrystallized in isopropyl ether and weighed after drying, yielding 13.5 g (yield 58%; Rf = 0.5-0.5 silica CH2Cl2/acetone/98/2).

The spectrum is identical to that obtained in f).

h) Preparation of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane

33 g of the compound obtained in f) or g) was suspended in 80 cm3 of 98% sulfuric acid and heated for 72 hours at 100ºC under an argon atmosphere. After cooling, the reaction mixture was added dropwise to 1 liter of ethyl ether at 0ºC. The obtained 2,6-dimethyl-1,4,7,10-tetraazacyclododecane sulfate was filtered, taken up in water, neutralized with Na2CO3 and extracted with CH2Cl2. The organic phases were evaporated to dryness. 6 g of the obtained product was used without further purification (yield 74%; Rf = 0.65 aluminum/butanol/water/acetic acid 50/25/11.

NMR spectrum (D2O): 6H CH3 (doublet 0.9 to 1 ppm); 14H CH2 and CH (multiplet center at 2.5 ppm).

i) Preparation of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N-N'-N'',N'''-tetraacetic acid

A mixture of 5.7 g (mmol) of monochloroacetic acid and 3.4 g (60 mmol) of potassium hydroxide in 25 cm3 of water is added to a solution of 3 g (15 mmol) of the compound obtained in h) in 25 cm3 of water. The resulting mixture is brought to 60 ºC and a solution of KOH (3.4 g, 60 mmol) in 25 cm3 of water is added so that the pH value is maintained between 9 and 10. The duration of the addition is 8 hours. The temperature is maintained for 24 hours after the addition of KOH. After cooling, the pH was adjusted to 2.5 with concentrated HCl. The formed precipitate was filtered, washed with ice water and measured after drying. 3 g is obtained (yield 35%; Rf = 0.33 silica/ethyl acetate/isopropanol/ammonia/12/35/30). This compound corresponds to the complex of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid with 2KCl.

9.5 g of the complex is eluted with 200 cm3 of 10% acetic acid on ion exchange resin IRA 95-(OH) previously regenerated with 1 NaOH and washed with water until neutral. The obtained fractions are evaporated to dryness and taken three times with 50 cm3 of water to eliminate traces of acetic acid. The obtained residue is rubbed with ether so that after filtering and drying it gives 6.3 g of a white solid substance. Yield: 89%.

NMR spectrum: (D2O)6HCH3 (doublet 1.4 and 1.5 ppm); 14H CH2 and CH (mass complex centered at 3.6 ppm); 8HCH2COOH (doublet at 3.8 ppm).

Example 2

Obtaining gadolinium complex 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''--tetraacetic acid (salt of methylglucamine)

A suspension of 5.425 g (12.54 mmol) of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid obtained in example 1 i) and 2, 27 Gd2O3 (6.27 mmol) in 125 cm3 of water is heated to 65 ºC for 24 hours. The pH is then adjusted to 7 by the addition of methylglucamine. After determining free Gd3+ by the xylenol/orange/EDTA method, 650 mg of 2,6-dimethyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (1.5 mmol) for complexing the remaining gadolinium. The end of complexation can be seen by the absence of free Gd3+ (determined by xylenol orange) and free complex (complexometric determination with Cu2+). The determination of total gadolinium in the solution is performed by atomic emission spectroscopy on DCP using the Spectrospan 4 Beckmann apparatus. Quantitative yield Rf = 0.49 silica/ethyl acetate/isopropanol/ammonia/12/35/30).

Example 3

Preparation of 2-hexyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid

a) Preparation of N-(2-hydroxyethyl)-N-(2-hexyl-2-hydroxyethyl)amine

50 g (0.39 mmol) of epoxy-1,2-octane is added dropwise to 250 cm3 (4 mol) of ethanolamine at 100 ºC. The temperature is maintained for 1 hour after the end of the addition, then the excess ethanolamine is distilled under vacuum. The residue is recrystallized from 600 cm3 of hexane and then filtered and dried. The resulting solid weighs 69 g (melting point below 45 ºC, yield 93% Rf = 0.82 silica (butanol/H2O/acetic acid/50/25/11).

NMR spectrum: 3H CH3 (triplet 0.9 ppm); 1OH CH2 (broad singlet at 2.2 ppm); 7H CH2 and CH (2 small signals at 2.8 and 3.8 ppm).

b) Preparation of N-tosyl-N-(2-tosyloxy ethyl)-N-(2-hexyl-2-tosyloxyethyl)amine

To a solution of 156 g (0.82 mol) of tosyl chloride in 300 cm3 of pyridine at 0ºC, 47.3 g (0.25 mol) of the compound obtained in a) is added in small portions for 1 hour. The mixture is kept at 0ºC for 2 days, then it is poured into a mixture of ice/HCl 2/1. The product is extracted with CH2Cl2, and then chromatographed on a silica column with CH2Cl2 as eluent. A mass of 118 g is obtained (yield 72%; Rf = 0.6 silica CH2Cl2/acetone/98/2).

NMR spectrum 3H CH3 chain (triplet at 0.9 ppm); 1OH CH2 chain (broad singlet at 1.3 ppm) 9H CH3 tosyl (singlet at 2.4 ppm); 4H CH2N (triplet Lodge resolved at 3.4 ppm CH2O and CH (massive at 4.2 ppm); 12H aromatics (massive between 7 and 7.7 ppm).

c) Preparation of N-tosyl-N-(2-azidoethyl)-N-(2-hexyl-2-azidoethyl)amine

87 g (0.133 mol) of the compound obtained in b) and 29.25 g (0.45 mol) of sodium azide are mixed in 350 cm3 of acetonitrile and 80 cm3 of water. The mixture is kept for 3 days at 65ºC. The acetonitrile is then evaporated under vacuum. The residue is taken up with CH2Cl2; the organic phase is washed in water, dried and evaporated; 50% of yellow oil is obtained, which is used without further purification. (yield: 95%; Rf = 0.75 silica/CH2Cl2/acetone/98/2).

NMR spectrum: 3H CH3 chain (triplet at 0.9 to 0.9 ppm); 1OH CH2 and CH (massive complex at 3.4 ppm), 4H aromatics (massive between 7.1 and 7.7 ppm).

The IR spectrum. N3 = 2100 cm-1 strong.

d) Preparation of N-tosyl-N(2-aminoethyl)-N-(2-hexyl-2-aminoethyl) amine

71 g (0.18 mol) of the diazide obtained in c) is poured into 500 cm3 of ethanol to which 5 g of palladium on carbon has been added at 50% moisture. The suspension is vigorously stirred under a stream of hydrogen for 24 hours. The catalyst is eliminated by filtration; after evaporation of the ethanol, 61.5 diamine is obtained, which is used without further purification (yield: quantitative; Rf = 0.51 silica/MeOH; NH4OH/95/5).

e) Preparation of N-tosyl-N(2-tosylaminoethyl)-N-(2-hexyl-2-tosyl-aminoethyl) amine

To a solution of 61.5 g (0.18 mol) of the compound obtained in d) in 500 cm3 of CH2Cl2 and 52.5 cm3 (0.38 mol) of triethylamine at 0ºC, 68.6 g (0.36 mol) of tosyl chloride was added in portions . After two hours of mixing at room temperature, the reaction mixture is treated with 500 cm3 of water. The organic phase is washed in water, dried, evaporated; the oily residue is chromatographed on a silica column with CH2Cl2 as eluent. After evaporation of the solvent, the obtained oil is taken with isopropyl ether to give 60 g of a white solid (melting point 120ºC; yield 51%; Rf = 0.6 silica/CH2Cl2/MeOH/98/2).

NMR spectrum; 13H hexyl chain (massively poorly decomposed centered at 1 ppm); 9H CH3 tosyl (singlet at 2.4 ppm); 7H CH2 and CH (massive centered at 3.1 ppm).

f) Obtaining N,N',N'',N'''-tetratosyl-2-hexyl-1,4,7,10-tetraazacyclododecane

A mixture of 46.5 g (71.5 mmol) of the compound obtained in d) above, 41.5 g (73 mmol) of the compound obtained in 1e) and 24 g (70 mmol) of tetrabutylammonium hydrosulfate is added to a suspension of 400 cm3 of toluene and 200 cm3 of 20% Na2CO3. The suspension is stirred vigorously at 70ºC for 24 hours. After cooling, the organic phase is washed with water, dried and evaporated. The residue is recrystallized in ethanol and then chromatographed on a silica column with CH2Cl2 as eluent.

35 g of solid substance is obtained (melting point 154-161ºC). Yield 56%; Rf = 0.55 silica/CH2Cl2/acetone/98/2).

NMR spectrum; 3H CH3 chain (triplet at 0.9 ppm); 10H CH2 chain (massive at 1.3 ppm); 12H CH3 tosyl (singlet at 2.4 ppm); 15H CH2 and CH ring (massive at 3.3 ppm); 16H aromatics (multiplet between 7.1 and 7.7 ppm).

g) Preparation of 2-hexyl-1,4,7,10-tetraazacyclododecane

12 g (13 mmol) of the compound obtained in f) is heated for 24 hours at 100ºC in 40 cm3 of 98% sulfuric acid under argon. After cooling, the mixture is poured dropwise into 500 ml of ethyl ether at 0ºC. The obtained sulfate is filtered and then neutralized with a 10% sodium carbonate solution and extracted with CH2Cl2. The organic phase was dried over sodium sulfate, then evaporated to give 2 g of solid cream. (yield: 57%; Rf = 0.75 aluminum/butanol/water (acetic acid 50/25/11).

The compound is stored in the form of oxalate, which is formed by reacting an ethanolic solution of oxalic acid with 2-hexyl-1,4,7,10-tetraazacyclododecane overnight at room temperature. Oxalate precipitates as a solid white substance.

h) Preparation of 2-hexyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid

A solution of 1.09 g (2 mmol) of oxalate obtained in g) in 13 cm3 of water and 20 ml of ethanol is neutralized with 470 mg (8.4 mmol) of KOH. Potassium monochloroacetate freshly prepared starting from 1.063 g (11.25 mmol) of monochloroacetic acid, 630 mg (11.25 mmol) of KOH in 20 cm3 is added to this solution.

The reaction mixture is heated to 60ºC and the pH is maintained between 8 and 10 by adding KOH. During 3 hours, 10 cm3 of water containing 630 mg of KOH is added. After 3 hours of reaction, 141 mg (1.5 mmol) of chloroacetic acid and 84 mg (1.5 mmol) of KOH are added.

The mixture is kept for another two days at 60ºC. After cooling, it is acidified to pH 2.5 (HCl 6N). The solution is passed through a column of OH-resin IRA 958. Elution with 100 cm3 of 10% formic acid yields 700 mg of product. Directly passed water is concentrated and re-treated on an identical column. After the same treatment, 2.5 g of product is obtained. (yield: 38.4%; Rf = 0.65 silica/ethanol/buffer/2/1).

NMR spectrum: 3H CH3 chain (triplet 0.9 ppm); 10H CH2 chain (massive at 1.4 ppm); 15H CH2 and CH cyclic (massive at 3.3 ppm); 8H CH2COOH (singlet at 3.9 ppm). Recording is done in D2O.

Example 4

Preparation of gadolinium 2-hexyl-1,4,7-tetraazacyclododecane-N,N',N'',N''-tetraacetic acid complex

488.6 mg (1 mmol) of the compound obtained in example 3 and 181.3 mg (1 meq.metal) of gadolinium oxide are suspended in 40 cm3 of water and kept at 65ºC for 2 days. During the reaction, the determination of free gadolinium allows monitoring the development of complexation. When complexation is complete, the solution is filtered on Millipore paper and then evaporated to dryness and crystallized from ethyl ether. 550 mg of a white solid is obtained (yield; 85.5%; Rf = 0.65 ETOH/buffer/2/1).

Example 5

Preparation of gadolinium 2-hexyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N''-tetraacetic acid complex (methylglucamine salt)

486.6 mg (1 mmol) of the compound obtained in example 3 and 181.3 mg (1 meq.metal) of gadolinium oxide are suspended in 40 cm3 of water and kept at 65ºC for 12 hours. Methylglucamine is added to the clear solution so that the pH is 7.4. In order to monitor the progress of complexation, this is added after the ligand. The end of complexation is determined by the absence of free Gd3+ (determination with xylenol orange) and free ligand (determination with copper). The total content of gadolinium in the solution is determined by atomic emission spectroscopy on the Spectrospan 4 Beckmann apparatus. Rf = 0.65 in EtOH/buffer/2/1.

Example 6

Preparation of 2-methyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid

a) Preparation of N,N'-ditosyl-1,2-diaminopropane

In a three-necked flask equipped with a magnetic stirrer, a thermometer and a chlorine shield, 14.8 g of 1,2-diaminopropane are dissolved in 500 ml of CH2Cl2 and 58 cm3 of Et3N.

Over the course of one hour, 80 g of tosyl chloride is added in portions. Cooling using an ice bath is required to maintain a temperature of 20ºC.

The reaction mixture is then stirred overnight at room temperature.

The reaction mixture is transferred by decanting into a 1-liter ampoule and then washed with 2 x 250 cm3 of water.

The organic fraction is dried over Na2SO4, evaporated to dryness, then crystallized in isopropyl ether.

The obtained mass is 66 g

Yield 86%

Melting point 98/100ºC

NMR

1ppm doublet (3H) 3.1 ppm massive (1H)

2.4 ppm singlet (6H) 5.5 ppm singlet variable (2H)

2.9 ppm doublet (2H) 7.1-7.8 ppm aromatic (8H)

CCM

SiO2 (silicon) eluent CH2Cl2 90 Rf = 0.75

MeOH 10

b) Preparation of N,N'-ditosyl-bis (2-tosyloxyethyl) ethylene diamine

A solution of 162 g of tosyl chloride in 300 ml of pyridine is cooled to 0 ºC in an ice and salt bath in a 500 cm3 three-necked flask equipped with a thermometer, chlorine protection and a magnetic stirrer.

At this temperature, 29.6 g of bis(2-hydroxyethyl)ethylenediamine are added in portions over 2 hours. The temperature must not exceed 5 ºC at any moment. The reaction mixture is stirred for 4 hours at this temperature, left for 48 hours at 6-8ºC in the fridge and then for 4 hours at room temperature.

The reaction mixture is added to a liter of ice, water and 300 ml of concentrated acid. The product is extracted with Na2SO4 and then evaporated to dryness. The residue is taken warm in 250 cm3 of ethanol. The product crystallizes. Strain through porous glass, dry at 60ºC for 48 hours.

The obtained mass is 107.5 g

Yield 70%

Melting point 138-140ºC

NMR

2.4 ppm singlet (12H)

3.3 ppm singlet + triplet (8H)

4.2 ppm triplet (4H)

7.2-7.8 ppm massive (16H)

CCM SiO2 plate eluent toluene 80 Rf = 0.6

acetone 20

c) Obtaining N,N',N'',N'''-tetratosyl-2-methyl-1,4,7,10-tetraazacyclododecane

A solution of 17.5 g of N,N'-ditosylamino-1,2-propane in 500 ml of dry DMF is mixed for 15 minutes in a three-necked liter flask at room temperature, then 33 g of previously powdered Ca2CO3 is added. The suspension is heated to 55 ºC using an oil bath under an inert atmosphere.

At this temperature, a solution of 35 g of N,N'-ditosyl-bis(2-tosylethyl)ethylene diamine in 500 ml of dry DMF is added dropwise over the course of 2 hours. After the addition is complete, the temperature is maintained for 48 hours. The DMF is then removed by distillation under vacuum. The residue is taken in a mixture of water/CH2Cl2.

The organic phase is dried over Na2SO4. The solvent is eliminated by distillation on a rotary evaporator.

The residue is stirred while warm in 200 ml of ethyl acetate. Wait for the product to crystallize. It is drained and then dried at 60ºC under vacuum for 24 hours.

The obtained mass is 22.5 g

Yield 61%

Melting point 274-275ºC

NMR

1 ppm doublet (2H)

2.2 ppm singlet (12H)

3-3.8 ppm massive (15H)

7.2-7.9 ppm massive (16H) aromatic

CCM

SiO2

eluent toluene 80

acetone 20

Rf = 0.56

d) Preparation of 2-methyl-1,4,7,10-tetraazacyclododecane

A solution of 72.5 g of the compound obtained in c) in 300 ml of 98% H2SO4 was heated at 100ºC for 48 hours using an oil bath under an inert atmosphere in a three-necked 1 liter flask equipped with a thermometer, an argon supply and a magnetic stirrer.

The reaction mixture is cooled to room temperature and after 1 hour is added to 800 ml of Et2O cooled to 0ºC using ethylene glycol and solid CO2.

Very hygroscopic sulfate precipitates. It is carefully strained under nitrogen on porous glass, then quickly dissolved in 200 ml of water. This solution is made alkaline with NaOH pellets and then extracted with 5 x 100 ml of CH2Cl2.

The combined organic phases are dried over Na 2 SO 4 and then evaporated to dryness to give 15 g of very viscous crude product which crystallizes with time.

Yield 90%

NMR

RDCI3 1.1 ppm doublet (2H)

Spectrum in D2O 2.7 ppm 2 singlet massive even 4 variable

CCM

plate Al203 eluent BuOH 50

H2O 55

ACOH 11

Rf = 0.8

e) Obtaining the complex of 2-methyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid with 2KCl.

In a 250 ml three-necked flask, cool a solution of 34 g of chloroacetic acid in 150 cm3 of water to 10ºC using an ice bath. At this temperature, 20 g of KOH is added to form the acid salt.

The compound obtained in d) is then dissolved in this solution. The reaction mixture is then heated to 65 ºC using an oil bath. At this temperature, for 6 hours, the pH is maintained between 8 and 10, a solution of 20 g of KOH in 50 cm3 of water is carefully added.

The temperature is then maintained for 72 hours, and the reaction mixture is acidified to pH 2.5 using concentrated HCl.

The complex is precipitated. It is drained on porous glass, washed with 50 cm3 of water and then dried at 60 ºC for 18 hours in an oven.

The resulting mass is 30 g

Yield 66%

Melting point above 300ºC

f) Purification of 2-methyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

30 g of the complex obtained in 2) is suspended in the presence of 150 cm3 of IRA 958 resin previously regenerated.

After dissolving the complex, this suspension is placed on top of a column containing 150 cm3 of IRA 958 resin.

Elution is performed using a solution of acetic acid in 5% water.

Fractions containing the product are evaporated to dryness in order to eliminate the starting acetic acid.

The obtained mass is 18.4 g

Yield 89%

Acidity 100.3 (4 equivalents) determined with 0.1 M NaOH

CCM

SiO2 eluent ACOET 12 Rf = 0.36

isopropanol 35

NH3, H2O 30

Mass spectrum FAB peak mass at M+1 = 419.

Example 7

Obtaining a solution of gadolinium complex 2-methyl-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (methylglucamine salt)

In order to dissolve 21 g (50 mmol) of the compound obtained in example 6 and 9.05 g (25 mmol) of gadolinium oxide in 50 ml of bi-distilled water, degassing is performed at 70ºC. After one hour the dissolution is complete, the pH is close to 3. After cooling, it is adjusted to 7.3 with methylglucamine. It is brought to 100 ml and filtered on a membrane with pores of 0.22 µm. A solution with a Gd content of 0.5 mol/l is then obtained. This solution has a viscosity at 20 ºC below 4 mPa s (free Gd is not defective).

Example 8

Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid

a) Preparation of N,N'-ditosyl-2,3-diaminopropionic acid

Add 40 g of 2,3-diamino propionic acid monochloride to a solution of 46 g of Na2CO2 in 500 cm3 of water with good mixing. Then 200 cm3 of ethyl ether is added and then 110.5 g of tosyl chloride is added in portions over one hour. Stirring is continued for 12 hours, the resulting precipitate is filtered and washed in water and ethyl ether. The resulting solid is suspended in 1 liter of water and acidified with 6N HCl. After filtering and washing with water and ethyl ether, the solid is dried for 24 hours at 60ºC under vacuum.

Obtained mass: 76 g

Yield: 65%

Melting point: 200-201ºC

CCM: SiO2 CH2Cl2 80/MeOH 20

Rf = 0.5

NMR

2.4 ppm singlet 6H (CH3 of the tosyl group)

2.8 ppm massive 3H (CH2, CH diamino chain)

3.5-5 ppm massive diffuse 3H exchangeable with D2O

7.2-7.8 ppm multiplet 8H aromatic

b) Preparation of N,N'-ditosyl-2,3-diaminopropanol

In a three-necked flask of 2 liters, a suspension of 40 g of the compound obtained in b) is mixed in 600 cm3 of THF at 20 ºC under an inert atmosphere without water (argon).

A solution of 500 ml of BH3 : THF 1M is added under an inert atmosphere during 1/2 hour. The temperature of the reaction medium rises to 30ºC. Mixing continues for 48 hours. Hydrolysis is carried out carefully with 20 ml of water. THF is eliminated by distillation under vacuum. The residue is extracted in a water/ether mixture. The organic phase is washed with water, dried over Na2SO4, then evaporated to dryness. The residue is triturated in isopropyl ether until crystallization. After squeezing and drying, 35 g of product is obtained.

Yield: 90%

Melting point: 126-127ºC

CCM: SiO2 CH2Cl2 90/MeOH 10

Rf: 0.6

NMR

2.7 ppm singlet "CH3" tozyl (6H)

3-3.7 ppm multiplet (7H of which two are interchangeable)

6.9 ppm triplet OH exchangeable alcohol (1H)

7.3-7.9 ppm multiplet aromatics (8H)

c) Obtaining n,N',N'',N'''-tetratosyl-2-hydroxymethyl-1,4,7,10-tetraazacyclododecane

In a 2-liter three-necked flask, dissolve 35 g of the compound obtained in b) in 1 liter of DMF-anhydride under nitrogen, then add 58.6 g of CaCO3 anhydride.

This suspension is stirred for 1 hour at room temperature and then heated to 65ºC using an oil bath. At this temperature, a solution containing 69 g of N,N'-ditosylbis(2-tosyloxyethyl)ethylene diamine in 600 cm3 of DMF anhydride is added dropwise over 6 hours. The temperature is maintained at 65ºC during the night; DMF is eliminated by distillation under vacuum. The residue is taken in a mixture of 400 ml of water and 400 cm3 of dichloromethane. The organic phase is decanted, washed with 200 cm3 of water, dried over Na2SO4, then evaporated to dryness. The oily residue was dissolved at 80ºC in 200 cm3 of toluene and then left in the fridge for 48 hours for crystallization. 24 g of product is obtained.

Yield: 32%

Melting point: 143-145ºC

CCM: SiO2 CH2Cl2 90/ACOET 10

Rf: 0.5

NMR

2.4 ppm singlet 12H CH3 tosyl

3.2-4.1 ppm massive 17 H CH2 ring+CH2-OH

7.2-8.1 ppm multiplet 16H aromatic

d) Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane

20 g of the compound obtained in c) is dissolved in 100 cm3 of 98% H2SO4.

This solution is heated to 100ºC for 48 hours under an inert atmosphere. The reaction mixture is cooled, then added dropwise to 1 liter of ethyl ether cooled using a dry CO2/acetone bath. The settled amine sulfate is filtered on porous glass and washed with ethyl ether. The solid substance is immediately dissolved in 200 cm3 of water, the solution is alkalized with NaOH to a pH above 12 and evaporated to dryness. After vacuum drying of the solid residue in the presence of P2O5, the product is extracted with 2x100 cm3 of THF at reflux. The extracted fractions were evaporated to give a colorless oil.

Obtained mass: 4.5 g of base

Yield: 90%

CCM: Al2O3 BuOH 50/water 25/AcOH 11

Rf: 0.8

NMR (CDCl3 spectrum)

2.8 ppm singlet (17H)+triplet

3.8 ppm singlet exchangeable (5H)

e) Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid

In a 250 cm3 three-necked flask equipped with a magnetic stirrer, a temperature probe and a pH-meter electrode connected to the pH-meter to control the pH of the medium, neutralize a solution of 8.5 g of the compound obtained in d), 15.8 g of 2-chloroacetic acid and 100 ml of water to pH+9.5 using a solution of 15.8 g of KOH in 50 cm3 of water. The reaction mixture is then heated to 50ºC using an oil bath for 72 hours. The pH is permanently maintained at 9.5 using a KOH solution. The mixture is cooled, acidified to pH=5, diluted to 500 cm3 and applied to a previously regenerated IRA 958 resin column that exchanges anions. The alkylation products bind to the resin. They are first washed with water, and then eluted with fractions of 5% acetic acid. The fraction is evaporated to dryness. The rest is a raw powder that is purified on a preparative HPLC column with a diameter of 40 filled with silicon RP.18.

Obtained mass: 3.5 g of pure product

Yield: 22%

Melting point: 142-144ºC

CCM: SiO2 AcEOT 112/isopropanol 35/NH4OH 30

Rf: 0.35

Acidity: 198.7% (2 reliability)

Determination with NaOH 0.1m H2O carrier

Mass spectrum FAB peak at M+1-377.

Example 9

Obtaining a solution of gadolinium complex 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10 triacetic acid

A suspension of 11.05 g of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid and 5.07 g of gadolinium oxide in bidistilled water is heated to 80°C for 1 hour.

After cooling, the pH was adjusted to 7.3 by adding K 2 CO 3 and the volume was adjusted to 100 ml. Determination of total gadolinium is performed by atomic emission spectroscopy (0.28 M/1).

Example 10

Preparation of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

In a 50 cm3 reactor equipped with a magnetic stirrer, a solution of 0.7 g of 2-hydroxymethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-triacetic acid and 0.28 g of chloroacetic acid in 15 cm3 of water at 70 oC.

The pH is adjusted to 10.5 using KOH solution and maintained at this value for 48 hours at 70 oC.

At the end of the reaction, the pH is adjusted to 5 and the solution is then eluted on IRA 958 resin.

The ligand is chromatographed on resin eluting with 5% acetic acid.

After evaporation to dryness, the product is purified using preparative HPLC (silicon RP18).

0.15 g of the ligand is then recovered in 18% yield.

CCM (silicon) eluent ethyl acetate 12

isopropanol 35 Rf = 0.25

NH3, H2O 30

Mass spectrum FAB peak at M+1 = 435.

Example 11

Preparation of 2-(2-hydroxyethyl)-1,4,7,10-tetraazacyclo-dodecane-N',N'',N'''-tetraacetic acid

This ligand is obtained according to the procedure described in examples 8 and 10, for the synthesis of 2-hydroxymethyl 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, starting from 3,4 -diaminobutyric acid (S.Kasina et al., J.Med.Chem. 29, 1993, 1986).

Example 12

Preparation of 2-methyl-1,4,7,10,13-pentaazacyclopentadecane-4,7,10,13-tetraacetic acid (product 12a) and 2-methyl-1,4,7,10,13-pentaazacyclopentadecane-1, 4,7,10,13-pentaacetic acid (product 12b)

a) Preparation of 1,4,7,10,13-pentatosyl-2-methyl-1,4,7,10,13-pentaazcyclopentadecane

35.7 g (0.093 mol) of N,N'-ditosyl-1,2-diaminopropane, 75.7 g of cesium carbonate (0.23 mol) and 800 ml of DMF.

The mixture was stirred under argon and then heated to 75oC.

A solution of 83 g (0.012 mol) of 1,11-mesyloxy-3,6,9-tritosyl-3,6,9-triazaundecane synthesized according to Ricman and Atkins, Organic Synthesis 58, p. 86, in 700 ml of DMF is added for 4 hours at 75oC.

The reaction mixture is maintained for 48 hours at 75oC and then the solution is concentrated to dryness.

The residue is taken up with 700 ml of ethanol, the solid substance is filtered and taken up in 800 ml of warm toluene.

The solid substance is filtered at room temperature and then dried at 60oC.

The result is: M = 45.4 g

Yield: 49%

Analysis: CCM: SiO2 60 F254 Merck

Eluent CH2Cl2/acetone 98.2 Rf = 0.45

mass spectrum

method D.I (NH3)

peak mass at 999.

b) Preparation of 2-methyl-1,4,7,10,14-pentaazcyclopentadecane

44 g (0.044 mol) of the compound obtained in a) is maintained for 72 hours at 100°C in 130 ml of concentrated sulfuric acid.

After cooling, the reaction medium is poured into a mixture of 250 ml of ethyl ether and 250 ml of ethanol at 0°C.

The solid substance is filtered, then dissolved in 250 ml of water and treated with carbon.

The solution is alkalized with Na2SO4 and evaporated to dryness.

Then the obtained amine can be used as such or in the form of hydrochloride.

It is obtained: M = 8.4 h in the form of a base

M = 13.2 g in the form with 5Hcl Rf: 72.8%

Hydrochloride analysis

CCM: Al203 F254 Merck

Eluent: ethanol/isopropylamine 80:20

reveals iodine

NMR: = 1.7 ppm 3 H CH 3

= 3.7 ppm 19H CH2 and CH

c) Preparation of 2-methyl-1,4,7,10,13-pentaazcyclopentadecane-4,7,10,13-tetraacetic acid (product 12a) and 2-methyl-1,4,7-pentaazcyclopentadecane-1,4, 7,10,13-pentaacetic acid (product 12b).

In a 500 ml three-necked flask, a solution of 25.7 g (0.27 mol) of chloroacetic acid in 50 ml of water is neutralized to pH=5 and at a temperature below 5 oC with 5M KOH.

10 g of the compound obtained in b) (10.043 mmol) dissolved in 20 ml of water is added to this solution.

The medium is heated to 55 oC and 50 ml of 5M KOH at pH 8.5-9.5 is added for 48 hours.

at the end of the addition, the temperature is maintained overnight

The reaction mixture is cooled and acidified to pH=3.

The solution is then applied to 200 ml of DOWEX 50w resin.

Elution of the resin with 1M ammonia solution yields 20 g of crude product.

The raw product is dissolved in 150 ml of water and applied to 250 ml of IRA 958 resin.

The resin is washed with water and then eluted with 2 liters of 0.1 M acetic acid and then eluted with 2 liters of 0.8 M acetic acid.

At an acetic acid concentration of 0.1 M, 9 g of crude product 12 a is obtained.

At an acetic acid concentration of 0.8 M, 12.5 g of crude product 12b is obtained.

Products 12a and 12b are then purified by preparative HPLC on silica RP18.

Obtained: Product 12a: M = 5 g

Product 12b: M = 1.1 g

Yield: 30%

Analysis: CCM: SiO2 d0F 254 merck

Eluent: ethyl acetate/isopropanol (NH3(30%)/12.35.30)

Proves: iodine

Product 12a Rf: 0.4

Product 12b Rf: 0.27

proving water:

Product 12a: KF: 1.8%

Product 12b: KF: 2.8%

Determination of acidity using 0.1M NaOH

Product 12a: 2 acidic functions

Titer: 99.6%

Product 12b: 3 acidic functions

Titer: 97.3%

Mass spectrum FAB

12a peak at M+1 = 462

12b peak at M+1 = 520

Claims (1)

1. Procedure for obtaining complexes formed with ligands of the general formula: [image] where: R1 represents the radical of the formula: [image] R6 is selected from the group consisting of C1-C14 alkyl, C1-C4 hydroxyalkyl, C1-C4 polyhydroxyalkyl and a group of the formula: [image] R11 is selected from groups A and groups of the formula -(CH2)t - Y - A - Y -(CH2)t - A is selected from the group consisting of C1-C8-hydroxyalkylene and C1-C8 poly-hydroxyalkylene [image] R7 is selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group, m = 0 or 1, R2, R3 and R4 are identical or different and represent the radical formula: [image] R8 and R9 are identical or different and are selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group and a C1-C4 polyhydroxyalkyl group, p = 1 or 2 n = 0, 1 or 2 and R5 is selected from the group consisting of a hydrogen atom, a C1-C4 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 polyhydroxyalkyl group, a group of the formula -CHR5-COOH, where R5 has the previously given meaning, and a group of the formula: [image] R 12 is selected from the group consisting of C1-C8 alkylene groups, C1-C8 hydroxyalkylene groups and C1-C8 polyhydroxyalkylene groups, and with metal ions selected from lanthanide ions with atomic numbers 57 to 71, with transition metal ions with atomic numbers 21 to 29 and with metal ions having atomic numbers 55, 56, 82 and 83, as for obtaining salts of these complexes with mineral bases or with organic pharmaceutically acceptable bases or with basic amino acids, indicated by the reaction of the compound of the formula: [image] in which R5 has the previously given meaning and X represents a labile group, or an aldehyde of the formula: R5 ─ CHO in which R5 has the meaning given above in the presence of hydrocyanic acid or cyanide ion, with a cylic amine of the formula: [image] in which R2, R3 and R4 and n have the meaning given above, R'1 represents the radical of the formula: [image] R'6 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 polyhydroxyalkyl and a group of the formula: [image] in which R2, R3, R4, R7, R11, m, n have the meaning given above and Z' is selected from the group containing an oxygen atom and a group of the formula: [image] R'10 is selected from the group consisting of a hydrogen atom, a C1-C14 alkyl group, a C1-C4 hydroxyalkyl group, a C1-C4 polyhydroxyalkyl group and a group of the formula: [image] in which R1, R2, R3, R4, R12 have the meanings given above, and then the ligand of formula I reacts with a salt or with an oxide of the above-defined metals in an aqueous solvent, and then eventually neutralization is carried out to form a salt.